The effectiveness of photodynamic therapy (PDT) depends on the simultaneous presence in the tumor tissue of photosensitizer, oxygen and light. In porphyrin-mediated PDT, tumor destruction can be achieved at low photosensitizer levels via relatively non- selective vascular collapse and ischemia. Direct photodynamic tumor cell inactivation, however, can be limited by the rapid vascular damage and development of tumor hypoxia. It is the long- term objective of this application to analyze the relationship between direct tumor cell effects and vascular effects in PDT tumor destruction, as well as to investigate the causes which lead to these effects. It is hypothesized that it would be beneficial for PDT treatment selectivity and effectiveness to identify ways by which the mechanism of tumor destruction could be shifted away from vascular effects towards a direct action upon tumor cells. To assess the validity of this hypothesis, the following studies will be carried out: Various newly developed photosensitizer (phthalocyanines, chlorophylls, cationic dyes) will be studied by established in vivo/in vitro methods with respect to their potential for direct photodynamic tumor cell inactivation in vivo, as well as for vascular damage and induction of tissue hypoxia. The possible involvement in the development of vascular PDT damage of arachidonic acid metabolites, a group of major vasoactive, inflammatory mediators, will be investigated by in vitro and in vivo methods. The photodynamic release of prostaglandin, prostacyclin, thromboxane and leukotrienes form macrophages, tumor, endothelial and smooth muscle cells, and platelets will be measured by radioimmunoassay. The possibility of protecting tissue from PDT-induced vascular and inflammatory effects by administration of inhibitors of arachidonic acid metabolite production (cyclooxgenase and lipoxygenase inhibitors) will be tested. The effects of such treatment on tumor response to PDT will be assessed.